The principle objective of the research proposed herein is the development of a new and general synthetic protocol for the preparation of a variety of biomedically significant alkaloids. Many seemingly unrelated compounds have a common structural subfeature; namely, a pyrrolidine or 3-pyrroline fused to another ring with the nitrogen at the bridgehead position. Examples include castanospemine (an inhibitor of glycoprotein processing which is currently being tested as an AIDS drug), indicine-N-oxide (an antitumor agent), slaframine (stimulates muscarinic cholinergic receptors), and gephyrotoxin (a neurotoxin exhibiting muscarinic antagonist activity). A flexible, common synthetic approach to these and many other alkaloids would be useful. Such a method has been developed during the previously funded period and will now be actually applied to the synthesis of the compounds mentioned above. Bicyclic 3-pyrrolines can be assembled in one step by the intramolecular cycloaddition of an azide onto a heterodiene. As a concurrent gaol, a method for the preparation of these materials in optically pure form is being developed. Many of these targets have several vicinal chiral centers, each bearing a heteroatom (oxygen,) nitrogen, or sulfur). A method for assembling these units with the correct stereochemical relationship was developed during the previously funded period, and will now be extended to the actual targets above. The method involves the fusion of certain heterocycles (1,3-dioxolan- 4-ones; 1,3-oxazolidin-5-ones; imidazolidin 3-ones; 1,3- oxathiazolidin-4-ones) to chiral auxiliaries in a rigid fshion, so that stereochemical information can be effectively transferred during carbon-carbon bond formations using enolate chemistry. In this way, alpha-hetero and alpha,beta-dehetero acids and their derivatives may be prepared. These may be used as chiral starting materials for alkaloid synthesis above, or will be used in the synthesis of other biomedically significant materials. Examples are carbohydrates such as KDO (a key structural component in the cell walls of Gram(-) bacteria), L-glucose (an L- sugar from the antitumor antibiotic bleomycin), and materials such as the antitumor agent bestatin and the gibberellin synergist LL-P880beta.